This invention generally provides a method for preventing, inhibiting, or treating vaginitis or bacterial vaginosis. More specifically, the present invention provides a method for preventing, inhibiting, or treating vaginitis and/or bacterial vaginosis using polystyrene sulfonate. The polystyrene sulfonate used in the present invention inhibits Trichomonas (a flagellate protozoon), Gardnerella, and other vaginitis/vaginosis-causing bacteria.
The female vagina is colonized by a variety of bacteria. Under normal conditions, the vagina flora provides a protective mechanism, including the maintenance of a low pH, to guard against the invasion of pathogenic microbes. A normal vagina generally contains more than about 104 lactobacilli per milliliter of vaginal material.
Infectious vaginitis is a common clinical syndrome and is diagnosed in more that 25 percent of women visiting sexually transmitted disease clinics. Common symptoms of infectious vaginitis include, for example, disruption of the normal vagina flora, irritation, odor, and/or vaginal discharge. Infectious vaginitis or vulvovaginities includes Candidiasis, trichomoniasis, bacterial vaginosis, and other vaginal infections. Bacterial vaginosis is the most common form of infectious vaginitis, accounting for 45 percent of symptomatic cases and estimated to be present in 15 percent of asymptomatic sexually active women. See, e.g., The Gynecologist and the Older Patient, Breen, J. (ed.), pp. 304-305 (1988); Principles and Practice of Infectious Diseases, Mandell, G. L., J. E, Bennett, and R. Dolin (eds.), vol. 1, ch. 95, pp. 1218-1235 (5th Edition, 2000); The Merck Manual of Medical Information: Home Edition, Berkow, R. (Editor-in-Chief, 1081-1083 (1997). Bacterial vaginosis is a polymicrobial vaginal infection believed to be caused by an increase in the number of anaerobic organisms with a concomitant decrease in lactobacilli in the vagina. The decrease in the number of lactobacilli in the vagina has a dual effect, i.e., (1) a decreased competition for nutrients and (2) a decrease in the amount of lactic acid present (i.e., increasing the pH), thus allowing for the multiplication of opportunistic pathogens in the vagina, whose growth is normally suppressed by the lactobacilli and the acidic pH of the vagina. The principal pathogens associated with bacterial vaginosis are believed to be Gardnerella vaginitis and other pathogenic anaerobes. Thus, bacterial vaginosis is considered a broad spectrum infection requiring a broad spectrum treatment.
Clinically, bacterial vaginosis presents itself as a superficial vaginal infection with no inflammatory response. Generally symptoms include an unpleasant smell, an elevated vaginal pH greater than about 5.0, a thin homogeneous discharge, and the presence of Gardnerella clue cells (i.e., vaginal epithelial cells coated with small Gram-variable rods). Generally, lowering the vaginal pH is an effective measure against the infection.
Generally, current treatment regimens for bacterial infection of the vagina, including vaginosis, involve the use of various broad spectrum antibiotics administered either topically or orally. The following table illustrates some of the current treatments for common vaginal/vulvar infections:
Antibiotics are generally undesirable, however, because they may kill a broad range of the normal bacterial flora in the vagina, including the beneficial lactobacilli. This may cause secondary complications, since the lactobacilli keep various opportunistic pathogens in the vagina in check. The treatment might then necessitate a further treatment regimen, such as the ingestion of cultured dairy products to replace the lactobacilli in the body, as well as treatment by antifungal agents. Moreover, a rise in the level of anaerobes due to a lack of lactobacilli could further complicate the infection. Additionally, antibiotics, when used frequently within the vagina, can cause systemic toxicity through absorption from the vagina.
More recently developed treatment regimes include those provided in U.S. Pat. No. 5,536,743 (Jul. 16, 1996) and U.S. Pat. No. 5,840,744 (Nov. 24, 1998) which used metronidazole in a buffered composition (pH maintained at about 3.75 to about 4.25) for intravaginal treatment of bacterial vaginosis. U.S. Pat. No. 6,017,521 (Jan. 25, 2000) provided a bioadhesive aqueous composition to control vaginal pH and, therefore, alleviate microorganism growth and odor such as presented by bacterial vaginosis.
U.S. Pat. No. 5,308,612 (May 3, 1994) provides a method using polystyrene sulfonate to inhibit or antagonize the transactivating transcription factor (Tat) of HIV/AIDS; the polystyrene sulfonate was reported to bock HIV replication as well as HIV viral adhesion and infection. U.S. patent application Ser. No. 09/252,417, filed Feb. 18, 1999, provides a method using polystyrene sulfonate for preventing sexually transmitted diseases (STDs) and/or reducing the rate of transmission of such sexually transmitted diseases; this method is especially adapted for use by sexually active individuals not at risk for pregnancy. U.S. patent application Ser. No. 09/252,417 is hereby incorporated by reference.
It would still be desirable, however, to provide improved methods for preventing, inhibiting, or treating vaginitis or bacterial vaginosis. It also would be desirable if such improved methods for preventing, inhibiting, or treating vaginitis or bacterial vaginosis did not involve the use of antibiotics. It would also be desirable if such methods would assist in obtaining or maintaining the natural and protective vaginal mechanisms. It would also be desirable if such methods would be relatively easy to use and have relatively few side effects. It would also be desirable if such methods utilize an active ingredient that is not absorbed, or only minimally absorbed, through the vagina lining, thereby greatly decreasing or eliminating the chance for systemic toxicity. The present invention, as detailed in the present specification, provides such methods.
This invention generally provides a method for preventing, inhibiting, or treating vaginitis or bacterial vaginosis. More specifically, the present invention provides a method for preventing, inhibiting, or treating vaginitis and/or bacterial vaginosis using polystyrene sulfonate. The polystyrene sulfonate used in the present invention inhibits Trichomonas (a flagellate protozoon), Gardnerella, and other vaginitis/vaginosis-causing bacteria.
The method of this invention generally comprises the application of an effective amount of an inhibitory agent into the vagina of a female in need of inhibition and/or treatment of vaginitis and/or bacterial vaginosis. Preferably the polystyrene sulfonate is contained in an aqueous based composition, and more preferably in an aqueous based composition buffered to a pH of about 3.5 to about 7.5, and even more preferably buffered at a pH of about 3.5 to 5.
The polystyrene sulfonate compositions of this invention can be used for treatment of active cases of vaginitis and/or bacterial vaginosis. Since the compositions of the present invention cause few, if any side effects, the polystyrene sulfonate compositions of this invention can also be used for prophylactic purposes. The polystyrene sulfonate used in the present invention is generally not toxic (or only minimally toxic) to natural and beneficial vaginal flora and, thus, does not significantly upset the local microbiological balance or significantly disrupt the protective glycoprotein vaginal coating. Disruption of the natural vaginal flora and/or removal or disruption of the protective glycoprotein vaginal coating using conventional vaginal compositions (e.g., contraceptives and the like) can lead to further irritation of the vaginal wall and/or lesions on the vaginal wall. Moreover, the preferred polystyrene sulfonate used in the present invention generally has a sufficiently high molecular weight to make vaginal absorption highly unlikely, thereby minimizing concern for systemic toxicity.
The present invention provides a method for the prevention, inhibition, or treatment of vaginitis and/or bacterial vaginosis in a female, said method comprising administering an effective amount of a polystyrene sulfonate composition into the vagina of the female.
The present invention also provides a method for the control and inhibition of Trichomonas, Gardnerella, or other vaginitis/vaginosis-causing bacteria in the vagina of a female, said method comprising administering an effective amount of a polystyrene sulfonate composition into the vagina of the female, wherein the effective amount of polystyrene sulfonate is sufficient to control and inhibit Trichomonas, Gardnerella, or other vaginitis/vaginosis-causing bacteria.
The present invention also provides a prophylactic treatment method for reducing the risk of vaginitis and/or bacterial vaginosis in a female, said method comprising administering an effective amount of a polystyrene sulfonate composition into the vagina of the female who may be at risk of vaginitis and/or bacterial vaginosis but is not suffering from vaginitis and/or bacterial vaginosis, wherein the effective amount of polystyrene sulfonate is sufficient to reduce the risk of Trichomonas, Gardnerella, or other vaginitis/vaginosis-causing bacteria from becoming established within the vagina.
The present invention also provides a method for the selective prevention, inhibition, or treatment of vaginitis and/or bacterial vaginosis in a female without significantly disrupting normal vaginal flora, said method comprising administering an effective amount of a polystyrene sulfonate composition into the vagina of the female, wherein the effective amount of polystyrene sulfonate is sufficient to inhibit Trichomonas, Gardnerella, or other vaginitis/vaginosis-causing bacteria without significantly disrupting normal vaginal flora.
Preferably the polystyrene sulfonate compositions used in the present invention comprise polystyrene sulfonate in an aqueous base buffered at a pH of about 3.5 to about 7.5, and even more preferably buffered at a pH of about 3.5 to 5. Preferably the polystyrene sulfonate composition contains about 10 to about 250 mg/ml polystyrene sulfonate having a molecular weight greater than about 100,000 g/mole. Even more preferably the polystyrene sulfonate composition contains about 20 to about 100 mg/ml polystyrene sulfonate having a molecular weight greater than about 200,000 g/mole.
These and other advantages of the present invention will be apparent from a consideration of the present specification.
This invention generally provides a method for preventing, inhibiting, or treating vaginitis or bacterial vaginosis. More specifically, the present invention provides a method for preventing, inhibiting, or treating vaginitis and/or bacterial vaginosis using polystyrene sulfonate. The polystyrene sulfonate used in the present invention inhibits Trichomonas (a flagellate protozoon), Gardnerella, and other vaginitis/vaginosis-causing bacteria.
The method of the present invention is carried out by applying an effective amount of polystyrene sulfonate into the vagina of a female needing, or desiring, such treatment. For purposes of this invention, an xe2x80x9ceffective amountxe2x80x9d is an amount of polystyrene sulfonate sufficient to inactivate, but not necessarily kill, bacteria or other microorganisms responsible for vaginitis or bacterial vaginosis on contact. Such bacteria or other microorganisms include, for example, Trichomonas, Gardnerella, and other vaginitis/vaginosis-causing bacteria.
Generally, the polystyrene sulfonate is incorporated into conventional carriers, such as, for example, lotions, creams, jellies, liniments, ointments, salves, oils, foams, gels, tablets, films, washes, suppositories, slow-releasing polymers, coatings, devices, and the like so that they can be easily applied topically in the present methods. The carriers may also include other ingredients such as, for example, pH modifiers, stabilizers, buffers, surfactants, moisturizers, colorants, thickeners, flavorings, fragrances, perfumes, and the like. The polystyrene sulfonate compositions of the present invention may be used by both sexually inactive and sexually active females. The polystyrene sulfonate compositions of the present invention may also be used with conventional birth-control or safe-sex devices. For example, the polystyrene sulfonate compositions could be incorporated into or simply used in conjunction with condoms (i.e., via lubricants applied to the interior and/or exterior surfaces), diaphragms, cervix caps, or similar products. The polystyrene sulfonate compositions of the present invention could also, for example, be released into the vagina by hand, via gels or suppositories, or by using conventional tampon or syringe techniques. The method of administering or delivering the polystyrene sulfonate composition into the vagina is not critical so long as an effective amount of polystyrene sulfonate is delivered in a timely manner. Preferably the formulations and/or method of delivering polystyrene sulfonate allows the polystyrene sulfonate compositions to remain within the vagina for an expended period of time (i.e., preferably for more than about 2 hours after administration) even during or after sexual activity in order to maximize the effectiveness.
Generally, the polystyrene sulfonate is employed at a concentration of about 5 mg/ml or higher in a suitable formulation, preferably at a concentration of about 10 mg/ml to about 250 mg/ml, and more preferably at a concentration of about 20 mg/ml to about 100 mg/ml based on the total weight of inert and active ingredients. Although it is generally preferred that the polystyrene sulfonate is used at noncytotoxic levels in order to minimize potential side effects, it can also be used, if desired, at levels at which bacteria or other microorganisms responsible for vaginitis or bacterial vaginosis (or a significant portion thereof) are effectively killed rather than simply inactivated or inhibited.
In actual use, polystyrene sulfonate in a suitable carrier or vehicle is applied, preferably topically, into vagina using any suitable technique (e.g., by hand, via gel or suppositories, or by using conventional tampon or syringe techniques). Of course, it is preferred that treatment begin as quickly as possible after the appearance of symptoms relating to vaginitis or bacterial vaginosis. The compositions of this invention can be reapplied as needed. Generally the composition is reapplied every about 12 to about 24 hours until control is obtained. For prophylactic purposes, treatment about once a day is usually sufficient. Of course, the frequency of application for either treatment or prophylactic purposes can vary with a number of factors, including, for example, the individual female and/or the severity of the infection.
The polystyrene sulfonate active ingredient used in this invention does not significantly affect or inhibit the growth characteristics of the normal vaginal flora or otherwise significantly irritate the vaginal tissue when used at inhibitory, noncytotoxic, or clinical concentrations. No toxicity was observed towards the host cells at the concentration ranges of polystyrene sulfonate used. Tests confirm there is essentially no effect on lactobacillus growth in the presence polystyrene sulfonate even at concentrations of up to about 5000 xcexcg/ml. Thus, the beneficial components of normal vaginal flora are not disrupted by the use of the present invention. Significant inhibition or modifications of the vaginal flora or other irritations (such as when nonoxynol-9 is used) can lead to increased risks of infections, unusual discharges, general discomforts, and the like, which, in turn, can lead to a reluctance to use or fully take advantage of the treatment method. Such inhibition or modifications of the vaginal flora can also lead to irritation of vaginal tissue and/or lesions which can actually increase the risk of infection by other undesirable organisms. Moreover, because the polystyrene sulfonate compositions of the present invention do not significantly disrupt normal vaginal flora, these compositions are ideally suited for use in prophylactic treatment regimes. Thus, a woman, based on her personal history, may wish to use these compositions in a prophylactic manner at times or during periods (e.g., during a particular period of her cycle or at a particular time of the year) when she is especially prone to vaginitis or bacterial vaginosis. Additionally, these compositions may also be used in a prophylactic manner after menopause when normal vaginal secretions may decrease.
Preferably the polystyrene sulfonates used in the present invention are prepared by free radical polymerization of sodium styrene sulfonate, thereby essentially eliminating chlorinated hydrocarbon contamination. Even more preferably, the free radical polymerization of sodium styrene sulfonate is carried out in a system which is essentially free of cross-linking agents (e.g., divinylbenzene). Polystyrene sulfonate prepared by this method generally retains a high solubility in water, thereby making it easy to incorporate in aqueous-based formulations, including aqueous-based gel formulations. If desired, the polystyrene sulfonate salt can be spray dried to form a white fluffy powder which can easily be incorporated into such formulations. Preferably the polystyrene sulfonates used in the present invention have molecular weights greater than about 100,000 g/mole, and more preferably in the range of about 200,000 to about 1,000,000 g/mole. The expected structure of a preferred polystyrene sulfonates suitable is a follows: 
Although the sodium salts are generally preferred, other alkali metal salts, alkaline earth salts, or amine salts can be used.
The polystyrene sulfonates suitable for use in this invention can also be obtained commercially; such commercial preparations are, however, preferably further purified before use. For example, a polystyrene sulfonate having a molecular weight of about 500,000 to 700,000 g/mole is available from National Starch (Bridgeport, N.J.) under the tradename Versa-TL 502. Generally, polystyrene sulfonate intended for industrial use (e.g., as an antistatic or emulsifying agent) may contain low levels of dichloroethane (ranging from about 50 to 700 ppm). For use in the present method, it is preferable that the dichloroethane levels are reduced to less than about 50 ppm and more preferably to less than about 10 ppm using suitable purification techniques.